This invention is directed to the use of quinolinyl phenyl compounds and their pharmaceutical compositions as PPAR-xcex3 ligand receptor binders, wherein PPAR-xcex3 ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR-xcex3 receptor.
Biological processes modulated by PPAR-xcex3 are considered biological processes which are modulated by receptor, or receptor combinations, which are responsive to the PPAR-xcex3 ligand receptor binders described herein. For example, cell differentiation to produce lipid accumulating cells, regulation of insulin sensitivity and blood glucose levels, which are involved in hypoglycemia/hyperinsulinism (resulting from for example, abnormal pancreatic beta cell function, insulin secreting tumors and/or autoimmune hypoglycemia due to autoantibodies to insulin, the insulin receptor, or autoantibodies that are stimulatory to pancreatic beta cells) and macrophage formation which lead to the formation of atherosclerotic plaques.
Two isoforms of PPAR-xcex3 receptor have been identified, namely PPAR-xcex31 and PPAR-xcex32, and are shown to differ in their amino termini.
Obesity is an excessive accumulation of adipose tissue. Recent work in this area indicates that peroxisome proliferator activated receptor-xcex3 (PPAR-xcex3) plays a central role in the adipocyte gene expression and differentiation. Excess adipose tissue is associated with the development of serious medical conditions, for example, non-insulin-dependent diabetes mellitus (NIDDM), hypertension, coronary artery disease, hyperlipidemia and certain malignancies. The adipocyte may also influence glucose homeostasis through the production of tumor necrosis factor xcex1 (TNFxcex1) and other molecules. One of the earliest events in the differentiation of an adipocyte is the expression of the xcex3 isoform of the PPAR-xcex3.
Non-insulin-dependent diabetes mellitus (NIDDM), or Phase II diabetes, is the most common form of diabetes, with 90-95% of the hyperglycemic patients experiencing this form of disease. In NIDDM there appears to be a reduction in the pancreatic xcex2-cell mass, several distinct defects in insulin secretion and a decrease in tissue sensitivity to insulin. The symptoms of this form of diabetes include fatigue, frequent urination, thirst, weight loss, blurred vision, frequent infections and slow healing of sores, diabetic nerve damage and renal disease.
Resistance to the metabolic actions of insulin is one of the key features of non-insulin dependent diabetes (NIDDM). Insulin resistance is characterised by impaired uptake and utilization of glucose in insulin-sensitive target organs, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose output. The relative insulin deficiency and the failure of insulin to surpress hepatic glucose output results in fasting hyperglycemia. The xcex2-cells in the liver try to compensate for the insulin resistance by secreting increased levels of insulin, however the xcex2-cells are unable to maintain this high output of insulin and eventually the glucose-induced insulin secretion falls, leading to the deterioration of glucose homeostasis and to the subsequent development of overt diabetes.
Hyperinsulinemia is also linked to insulin resistance, hypertriglyceridaemia and increased plasma concentration of low density lipoproteins. The association of insulin resistance and hyperinsulinemia with these metabolic disorders has been termed xe2x80x9cSyndrome Xxe2x80x9d and as been strongly linked to an increased risk of hypertension and coronary artery disease.
Metformin is known in the art to be used in the treatment of diabetes in humans (U.S. Pat. No. 3,174,901). Metformin acts primarily to decrease the patient""s liver glucose production. Troglitazone is known to work primarily on enhancing the ability of the patient""s muscle to respond to insulin and take up glucose. It is known that combination therapy comprising metformin and troglitazone can be used in the treatment of abnormalities associated with diabetes (Today""s News Connection, AAAS EurekaAlert Press Releases, Mar. 26, 1996).
The present invention discloses a series of compounds for use in stimulating insulin sensitization and providing glycemic control, as well as a number of other pharmaceutical uses associated with it.
An object of this invention is the use of quinolinyl phenyl compounds and their pharmaceutical compositions as PPAR-xcex3 ligand receptor binders, which are useful as agonists or antagonists of the PPAR-xcex3 receptor.
The quinolinyl phenyl compounds for use according to the invention are of formula I 
wherein:
A is O, S 
xe2x80x83or a chemical bond;
B is O, S, SO, SO2, NR1, a chemical bond, 
D is O, S, NR1, 
xe2x80x83or a chemical bond;
E is a chemical bond or 
a is 0-2;
b is 0-1;
c is 0-4;
d is 0-5;
e is 0-4;
f is 0-5;
n is 0-2;
R is independently hydrogen, alkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl, halo, nitro, cyano or acyl;
Rxe2x80x2 is independently hydrogen, alkyl, hydroxy, alkoxy or halo;
R1 is independently hydrogen, alkyl or aralkyl, or geminal R1 and R1 taken together with the carbon atom to which the geminal R1 and R1 are attached to form xe2x95x90CHR1;
R2 is xe2x80x94(CH2)qxe2x80x94X, or two vicinal R2 taken together with the carbon atoms through which the two vicinal R2 are linked form cycloalkylene, or geminal R1 and R2 taken together with the carbon atom to which the geminal R1 and R2 are attached form cycloalkylene, xe2x95x90CHR1, or carbonyl;
q is 0-3;
X is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxy, alkoxycarbonyl, tetrazolyl, acylHNSO2xe2x80x94, Y1Y2Nxe2x80x94 or Y3Y4NCOxe2x80x94;
Y1 and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one of Y1 and Y2 is hydrogen or alkyl and the other of Y1 and Y2 is acyl or aroyl;
Y3 and Y4 are hydrogen, alkyl, aryl, aralkyl or heteroaralkyl;
Z is R1O2Cxe2x80x94, CN, halo, R3O2SHNCOxe2x80x94, (R1)2NCOxe2x80x94,R1Oxe2x80x94 or tetrazolyl; and
R3 is hydrogen, alkyl, phenyl or benzyl, or
a pharmaceutically acceptable salt thereof.